The growing use of the MAO inhibiting drugs, expecially phenelzine sulfate, in the treatment of depression and other affective neuroses in clinical practice warrants additional study to investigate the pharmacokinetics and metabolism of this drug. Despite the fact that phenelzine has been an approved drug for approximately 20 years, there are few studies of its metabolism in animal or in man. This proposal is to synthesize stable isotope labelled phenelzine analogs for use in vivo experiments and as an internal standard in GC/MS assays. The first analogs to be synthesized will be used in studies to extablish the major metabolic pathways of phenelzine by determining urine metabolite patterns. A second stable isotope labelled phenelzine analog will be used to examine pharmacokinetic profiles in the drug-free and the chronically treated patient and in matched normal controls. Evidence for the nonlinear kinetics of phenelzine and its gradual accumulation in plasma over the first several weeks of drug treatment will be examained and related to platelet MAO inhibition. Study findings will be used to develop dosage guidelines for phenelzine, both for the initial treatment period using a modified loading dose strategy, and for maintenance phenelzine treatment after the acute depressive episode has resolved. The investigators have carried out prior studies which strongly suggest that phenelzine is in part metabolized by the enzyme, monoamine oxidase, such that its half-life is dose dependent and markedly prolonged after the initial weeks of treatment. Methods for the synthesis of the stable isotope labelled phenelzine have been worked out and demonstrated to be practical with high yield. Because of the evidence for specific MAOI responsive patients and syndromes, it is important to define the metabolism of phenelzine, one of the most widely used MAO inhibitors. By defining its drug metabolism and time-dependent pharmacokinetics, it should be possible to devise a rational dosing strategy which can reduce the lag between initiating drug treatment and initial clinical response, and also to develop guidelines for maintenance therapy which will maintain levels of platelet MAO inhibition and plasma phenelzine within an effective therapeutic range. The proposed study should provide a basis for the proper administration of phenelzine in clinical practice.